Psychedelic drugs produce profound states of altered consciousness and show promise for treating mental health disorders. These drugs promote synaptogenesis, increase neurite outgrowth, and increase spine size, processes which are thought to underlie their beneficial long-term effects. Psychedelics structurally resemble the neuromodulators serotonin and dopamine, and indeed the prevailing theory of psychedelic mechanism of action is agonism of 5-HT2A receptors. However, psychedelics are so potent, long-lasting, and varied in their effects on cognition and neuroplasticity that additional mechanisms seem likely. We hypothesized that in addition to binding to receptors, psychedelic drugs, like amine neuromodulators, are chemically reactive and can covalently react with specific glutamine residues of diverse proteins through enzymatic addition.

To test this hypothesis, we utilized click-chemistry compatible psychedelic analogs of both tryptamines and phenethylamines. These analogs allow the downstream incorporation of functional groups such as a fluorophore for microscopy or an affinity tag for purification and proteomics analysis. Visualization of the analogs in cultured human neurons revealed a rapid localization to the nucleus. Using larval zebrafish we are conducting a brain wide analysis of drug localization. Purification and proteomic analysis of covalent drug interactions in human neurons showed an enrichment of nuclear proteins, including Histone H3. A nuclear function of psychedelics was further supported by phospho-proteomics of human neurons treated with parent compounds. Further research is needed to determine the functional consequences of protein modification by psychedelic drugs. We predict that an epigenetic mechanism could underlie the beneficial long-term effects of a single administration of a psychedelic drug.